Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001838022 | SCV000777019 | uncertain significance | Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1 | 2018-05-29 | criteria provided, single submitter | clinical testing | This variant, c.8187_8193delinsAGATTTA, is a complex sequence change that results in the deletion of 3 amino acids of the APOB protein and the insertion in 3 additional ones (p.Asn2729_Phe2731delinsLysAspLeu). This variant is reported as two separate single-nucleotide changes in population databases (c.8187T>A, ExAC 0.001% and c.8193T>A, ExAC 0.001%). However, in the read data for 3 individuals displayed in the gnomAD browser, these two variants are in cis. This recapitulates the variant observed here (c.8187_8193delinsAGATTTA) and indicates that this variant is very likely present in the population databases at 0.001%. This variant has not been reported in the literature in individuals with APOB-related disease. The Lys-Asp-Leu amino acid residues are found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |